EP0394685A2 - Acide-(S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique - Google Patents

Acide-(S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique Download PDF

Info

Publication number
EP0394685A2
EP0394685A2 EP90105827A EP90105827A EP0394685A2 EP 0394685 A2 EP0394685 A2 EP 0394685A2 EP 90105827 A EP90105827 A EP 90105827A EP 90105827 A EP90105827 A EP 90105827A EP 0394685 A2 EP0394685 A2 EP 0394685A2
Authority
EP
European Patent Office
Prior art keywords
amino
dihydro
oxo
fluoro
cyclopropyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90105827A
Other languages
German (de)
English (en)
Other versions
EP0394685A3 (fr
Inventor
Joseph Peter Sanchez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP0394685A2 publication Critical patent/EP0394685A2/fr
Publication of EP0394685A3 publication Critical patent/EP0394685A3/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • US Patent 4,649,144 discloses 7-(3-amino-­1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro­4-oxo-1,8-naphthyridine-3-carboxylic acid as having antibacterial activity.
  • the patent it is recognized that there is an asymmetric carbon atom on the pyrrolidine ring of the compound and that the compound can exist in optically active forms. Nevertheless, the patent does not describe the synthesis of these optically active forms nor does it describe or suggest which, if any, of the optically active forms would have antibacterial activity equal, better or less than the racemic compound, the compound specifically described in the patent.
  • the present invention is directed to the S optical isomer of 7-(3-amino-1-pyrrolidinyl)-­1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyri­dine-3-carboxylic acid, its lower alkyl esters or a pharmaceutically acceptable acid addition or base salt thereof.
  • the present invention also concerns a pharmaceutical composition containing the above compound together with a pharmaceutical excipient in a dosage form for treating bacterial infections.
  • the present invention is directed to a method of preparation of pharmaceuticals for treating bacterial infections in mammals by administering to said mammal in need thereof an antibacterially effective amount of the above compound in unit dosage form.
  • Compounds of the present invention may be readily prepared by treating a 7-halo-1-cyclopropyl-6-fluoro-­1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or a lower alkyl ester wherein lower alkyl is one to four carbon atoms, with an (S)-3-[[lower alkyloxy-­carbonyl]amino]pyrrolidine in the presence of base and optionally in the presence of an organic solvent at approximately ambient to somewhat elevated temperatures, e.g., 25-100°C.
  • blocking groups in addition to lower alkyloxycarbonyl groups, can be formyl, acetyl, trifluoroacetyl; ⁇ , ⁇ , ⁇ -trichloroethoxycarbonyl, ⁇ -iodoethoxycarbonyl; aryloxycarbonyl group such as benzyloxycarbonyl, p -methoxybenzyloxycarbonyl, phenoxycarbonyl; silyl groups such as trimethylsilyl; and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o -nitrophenyl, sulfenyl, diphenylphosphinyl, p -toluenesulfonyl, and benzyl.
  • the groups may be removed by acid hydrolysis but also can be removed by base hydrolysis, and the trityl group, for example, may be removed by hydrogenolysis.
  • reaction between the protected aminopyrrolidine and the haloquinoline can be carried out in a range of from 20°C to about 150°C; higher temperatures usually require shorter reaction times and may be prepared from known starting materials by standard procedures or by variations thereof.
  • 7-chloro-1-cyclopropyl-6-fluoro-­1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid may be prepared by a series of reactions starting from 4-(6-chloro-3-nitro-2-pyridinyl)-1-piperazinecarboxylic acid, ethyl ester.
  • the intermediate, 1-cyclopropyl-­6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naph­thyridine-3-carboxylic acid can be converted to the 7-hydroxy derivative with a mixture of nitric and sulfuric acids which is then replaced by chlorine by treatment with phosphorus oxychloride to give the desired intermediate.
  • the synthesis of both of the above N-cyclopropyl intermediates is described in the Preparative Examples.
  • the (S)-protected aminopyrrolidine may be prepared in accordance with the procedures described in the examples herein.
  • the compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts.
  • Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • heavy metal salts such as for example silver, zinc, cobalt, and cerium. Such heavy metal salts are effective in the treatment of burns especially when applied to the affected surface of a burn victim either directly or in combination with a physiologically acceptable carrier such as a water dispersible, hydrophilic carrier.
  • suitable amines are N,N′dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
  • Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the like.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt form with a base.
  • dilute solutions of aqueous base may be utilized.
  • Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Use of excess base gives the corresponding basic salt.
  • the compounds of the invention can exist in un­solvated as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms and the like are equivalent to the unsolvated forms for purposes of the invention.
  • alkyl groups contemplated by the invention comprise both straight and branched carbon chains of from one to about three carbon atoms except when specifically stated to be greater than three carbon atoms.
  • Representative of such groups are methyl, ethyl, propyl, isopropyl, and the like.
  • alkoxy groups contemplated by the invention comprise both straight and branched carbon chains of from one to about six carbon atoms unless otherwise specified. Representative of such groups are methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, hexoxy, and the like.
  • halogen or halo is intended to include fluorine, chlorine, bromine, and iodine unless otherwise specified.
  • the compounds of the invention can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, a compound of the present invention or a corresponding pharmaceutically acceptable salt thereof.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • Ointment preparations contain heavy metal salts of a compound of Formula I with a physiologically acceptable carrier.
  • the carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion which may be applied to an affected burn surface or infected surface with a minimum of discomfort.
  • Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package con­taining discrete quantities of preparation, for example, packeted tablets, capsules, powders in vials or ampoules, and ointments in tubes or jars.
  • the unit dosage form can also be a capsule, cachet, tablet, gel or cream itself or it can be the appropriate number of any of these packaged forms.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily.
  • a daily dose range of about 6 mg to about 14 mg per kilogram is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circum­stances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds of the invention display antibacterial activity when tested by the microtitration dilution method as described in Heifetz, et al, Antimicr. Agents and Chemot. 6 , 124 (1974), which is incorporated herein by reference.
  • the following minimum inhibitory concentration values MICs in ⁇ g/ml
  • PD50 median protective doses
  • Therapeutic activities of the compounds were compared in acute mouse protection tests in which 18-22 g female Charles River CD-1 mice were used. Oral and subcutaneous doses in twofold rising incremental series were administered concurrently with bacterial challenge. Challenges were accomplished by the intraperitoneal injection of an estimated 100 median lethal doses in 0.5 ml volumes of 5% hog gastric mucin or tryptic soy broth. Generally, greater than 90% of the untreated controls died within 48-72 hours. Final survival percentages, obtained after 4-7 days of observation among groups of 8-16 mice, were used to estimate median protective doses (PD50) by the log-probit method. "S" Isomer "R” Isomer Racemic PD50 PD50 PD50 Organisms MIC P.O. S.C.
  • reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (2 x 500 ml).
  • the combined organic layers were washed with 1.0 N sodium hydroxide (4 x 50 ml), water, dried (MgSO4) and evaporated in vacuo to give 17.5 g of the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19900105827 1989-03-28 1990-03-27 Acide-(S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique Withdrawn EP0394685A3 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/329,461 US4916141A (en) 1989-03-28 1989-03-28 (S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
US329461 1994-10-26

Publications (2)

Publication Number Publication Date
EP0394685A2 true EP0394685A2 (fr) 1990-10-31
EP0394685A3 EP0394685A3 (fr) 1991-09-25

Family

ID=23285509

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900105827 Withdrawn EP0394685A3 (fr) 1989-03-28 1990-03-27 Acide-(S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique

Country Status (12)

Country Link
US (1) US4916141A (fr)
EP (1) EP0394685A3 (fr)
JP (1) JP2948857B2 (fr)
KR (1) KR900014382A (fr)
AU (1) AU617974B2 (fr)
CA (1) CA2013136C (fr)
FI (1) FI94640C (fr)
NO (1) NO175369C (fr)
NZ (1) NZ233087A (fr)
PH (1) PH26185A (fr)
PT (1) PT93571B (fr)
ZA (1) ZA902356B (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5057523A (en) * 1988-09-22 1991-10-15 Abbott Laboratories Dipeptide quinolone derivatives
US5057520A (en) * 1989-03-24 1991-10-15 Abbott Laboratories 7-(peptidylpyrolidinyl)naphthyridine antibacterial compounds
US5177217A (en) * 1992-04-27 1993-01-05 Warner-Lambert Company Process for the manufacture of (S)-3-amino-1-substituted-pyrrolidines
US5290794A (en) * 1992-10-27 1994-03-01 Warner Lambert Co. Soluble calcium lactate antibacterial complexes as non-irritating parenteral forms
US5977381A (en) * 1998-01-12 1999-11-02 Hoffmann-La Roche Inc. Process for making 3-amino-pyrolidine derivatives
KR100295740B1 (ko) 1998-09-17 2001-11-05 박영구 N-치환된-하이드록시고리화알킬아민유도체의제조방법
CA2491133C (fr) * 2002-08-01 2009-09-01 Basilea Pharmaceutica Ag Procede relatif a l'elaboration de derives d'amino-pyrrolidine
KR100939347B1 (ko) * 2005-07-20 2010-01-29 (주)카이로드 광학적으로 순수한 (ｓ)-3-히드록시 피롤리딘의 제조방법
EP2050735A4 (fr) 2006-07-28 2011-12-21 Kaneka Corp Méthode de production d'un composé 3-amino-azoté optiquement actif
JP5779100B2 (ja) 2008-11-24 2015-09-16 カウンシル オブ サイエンティフィック アンド インダストリアル リサーチ 光学的に活性なｎ−ベンジル−３−ヒドロキシピロリジンの製造方法
EP4382529A1 (fr) 2022-12-07 2024-06-12 Bayer Consumer Care AG Procédé de préparation de (3s)-pyrrolidin-3-ol pur et de chlorhydrate de (3s)-pyrrolidin-3-ol pur

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS274601B2 (en) * 1983-07-27 1991-09-15 Dainippon Pharmaceutical Co Method of 1,8-naphthyridine derivative production
ZA877471B (en) * 1986-10-08 1988-04-05 Bristol-Myers Company 1-tertiary-alkyl-substituted naphthyridine-and quinoline-carboxylic acid antibacterial agents
US4851418A (en) * 1987-08-21 1989-07-25 Warner-Lambert Company Naphthyridine antibacterial agents containing an α-amino acid in the side chain of the 7-substituent
AU5123690A (en) * 1989-03-13 1990-09-13 Bristol-Myers Squibb Company 5-substituted-1,4-dihydro-4-oxo-nephthyridine-3-carboxylate antibacterial agents

Also Published As

Publication number Publication date
EP0394685A3 (fr) 1991-09-25
NO175369B (no) 1994-06-27
JP2948857B2 (ja) 1999-09-13
ZA902356B (en) 1991-11-27
PT93571A (pt) 1990-11-07
AU5219790A (en) 1990-10-04
AU617974B2 (en) 1991-12-05
FI94640C (fi) 1995-10-10
FI901505A0 (fi) 1990-03-26
JPH02289568A (ja) 1990-11-29
US4916141A (en) 1990-04-10
CA2013136A1 (fr) 1990-09-28
NO175369C (no) 1994-10-05
FI94640B (fi) 1995-06-30
NO901391L (no) 1990-10-01
KR900014382A (ko) 1990-10-23
NZ233087A (en) 1991-07-26
NO901391D0 (no) 1990-03-27
CA2013136C (fr) 1998-09-15
PT93571B (pt) 1996-08-30
PH26185A (en) 1992-03-18

Similar Documents

Publication Publication Date Title
US4851418A (en) Naphthyridine antibacterial agents containing an α-amino acid in the side chain of the 7-substituent
EP0326891B1 (fr) Agents antibactériens
JP2917010B2 (ja) 光学活性ピリドンカルボン酸誘導体
US4735949A (en) Disubstituted-7-pyrrolidinonaphthyridine antibacterial agents
RU2100351C1 (ru) Производные пиридонкарбоновой кислоты и композиция на их основе
US5654318A (en) Bicyclic amine derivatives
US4916141A (en) (S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
JPH01319463A (ja) ７―置換キノロン―及びナフチリドン―カルボン酸誘導体
KR100531967B1 (ko) 트리사이클릭 아민 유도체, 이를 포함하는 항균제 및 퀴놀론 화합물의 제조방법
JP4094061B2 (ja) シス置換アミノシクロプロパン誘導体
US5157128A (en) Certain optically active substituted α,α-dialkyl-pyrrolidine-3-methamines useful as intermediates
KR950007590B1 (ko) 7-(1-피롤리디닐)-퀴놀론카르복실산 유도체의 제조 방법
JPWO1998002431A1 (ja) シス置換アミノシクロプロパン誘導体
US5072001A (en) Certain optically active substituted 3-pyrraidine acetic acid derivatives useful as intermediates
JPH02290870A (ja) 対掌体的に純粋な７‐（３‐アミノ‐１‐ピロリジニル）‐キノロン‐および‐ナフチリドンカルボン酸
JPWO1998054169A1 (ja) 置換シクロブチルアミン誘導体
KR100458146B1 (ko) 사이클로알킬아미노메틸피롤리딘유도체및이를유효성분으로하는항생제
US5364861A (en) Optical isomers of 7-[3-(1,1-dialkylmethyl-1-amino-1-pyrrolidinyl]-quinolones and naphthyridones as antibacterial agents
JPH051073A (ja) 光学活性ピリドベンゾオキサジン誘導体
JP4926723B2 (ja) フルオロアルキルピロリジン誘導体
JP4619952B2 (ja) ８−シアノキノロンカルボン酸誘導体
KR19980076903A (ko) 신규한 퀴놀론카르복실산 유도체
JPS6124572A (ja) 新規キノリンカルボン酸誘導体、その製造法およびそれを有効成分とする抗菌剤

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19900327

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19930513

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19961001